Metacyclophane1

CONTENTS

468

Formation of N-acyl-N,N'-dicyclohexylureas from DCC and arenecarboxylic acids in the presence of hydroxybenzotriazole in CH2Cl2 at room temperature.

O / C R

Carlos R. Kaiser, Alessandra C. Pinheiro, Marcus V. N. de Souza, James L. Wardell and Solange M.S.V. Wardell

473

N R

O C NHR

CH3

Convenient synthesis of 2-pyridyl thioglycosides

CH3 CN

R5

CN

R5 NH3/CH3OH

N

R

6

S

R1

476

R2

S

R1

OAc

Galal Elgemeie, Elsayed Eltamny, Ibraheim Elgawad and Nashwa Mahmoud

N

R6

O

O OH

R2

OAc

OH

The rotation of the nitro and formyl groups relative to the aromatic ring in some orthonitroarylaldehydes

James R. Hanson, Peter B. Hitchcock and Francois Toche MeO

479

Synthesis and structures of [2.n]metacyclophane-1,2-diones

MeO

OH H

O DMSO-Ac2O

[CH2]n H

[CH2]n

room temp. for 20 h

O

OH

MeO

MeO

MeO

H2N

N

H2 N

Tatsunori Saisyo, Mikiko Shiino, Tomoe Shimizu, Arjun Paudel and Takehiko Yamato

484

in EtOH room temp. for 24 h (quant)

Synthesis of 14-aryl-14H-dibenzo[a,j ]xanthene derivatives catalysed by expanded graphite under solvent-free condition

[CH2]n N MeO

OH expanded graphite

ArCHO + 2

Ar

120 oC O

Geng-Chen Li

486

An efficient synthesis of N,N-bis[2-(2-nitropheny lamino)ethyl]glycine glycosyl esters and antiviral activity NHCH2CH2

NCH2COOH

NO2 2

Hong Chen, Si-Qing Huang and Jian-Ying Xie

GL-Br DMAP/Et3 N

NHCH2CH2

NCH2COOGL

NO2 2

JOURNAL OF CHEMICAL RESEARCH 2008

AUGUST, 479–483

RESEARCH PAPER

479

Synthesis and structures of [2.n]metacyclophane-1,2-diones Tatsunori Saisyo, Mikiko Shiino, Tomoe Shimizu, Arjun Paudel and Takehiko Yamato* Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan

McMurry cyclisation of 1,n-bis(5-formyl-2-methoxyphenyl)alkanes afforded dimethoxy[2.n]metacyclophan-1-enes and dimethoxy[2.n]metacyclophane-1,2-diols, in which latter one was converted to dimethoxy[2.n]metacyclophane1,2-diones by Albright–Goldman oxidation.

Keywords: cyclophanes, McMurry reaction, [2.n]metacyclophane-1,2-diol, conformation, oxidation, 1,2-diketones For many years various research groups have been attracted by the chemistry and spectral properties of the [2.2]MCP >@0&3  >@PHWDF\FORSKDQH  VNHOHWRQ1-3 Its conformation, which was elucidated by X-ray measurements,4 is frozen into a chair-like non-planar form. Many attempts have been made directly to introduce functional groups into the methylene groups of [2.2]MCPs, but these have failed because of the deviation of the benzyl carbon atom from the plane of the benzene ring.5–11 Singler and Cram12 have reported that bromination of [2.2]paracyclophan-1-ene with bromine affords the corresponding cis-adduct. Recently, we have reported that di-tert-butyldimethyl[2.n]MCP-1-enes were treated with an equimolar amount of benzyltrimethylammonium tribromide (BTMA Br3) in methylene dichloride to afford the cis-adducts to the bridged double bond.13–167KLVUHVXOWLQGLFDWHVWKH¿UVW success in the introduction of two bromo groups into the methylene groups of dimethyl[n.2]MCPs. We have extended the novel reaction mentioned above and reported on the acetolysis of bromine adducts with silver acetate in acetic acid and the conversion to dimethyl[2.n]MCP-1,2-diones via hydrolysis followed by Swern oxidation of the dihydroxy derivatives.17 However, we have not yet succeeded in preparing [2.2]MCP-1,2-dione due to the novel transannular reaction arising from the electronic interaction between two benzene rings, the proximity of the 8,16-positions and the release of the considerable strain energy to form the more stable annulene S-electron system, 10b,10c-dihydropyrene. Thus, the reaction of 5,13-di-tert-butyl-8,16-dimethyl[2.2]MCP-1-ene13 with bromine affords 4,5,9,10-tetrabromo-2,7-di-tert-butyl-trans10b,10c-dimethyl-10b,10c-dihydropyrene in good yield, but not the adduct to the bridged double bond, which can be converted to the corresponding [2.2]MCP-1,2-dione.14 On the other hand, in cyclophane chemistry, the reductive coupling of carbonyl compounds by low-valent titanium, the McMurry reaction,18–21 has been used before by Mitchell and Weerawarna22 to synthesise cyclophanes with glycol units as bridges, by Tanner and Wennerström,23 and recently by Hopf and Mlynek,24 and Grützmacher and Neumann25 for a cyclisation of suitable dialdehydes to yield unsaturated cyclophanes. Thus, there is substantial interest in the developing a more convenient preparation of [2.n]MCP-1enes or 1,2-diols than the conventional sulfur method.13–16 We report here on the use of the McMurry coupling reaction to prepare a series of [2.n]MCP-1,2-diols and their conversion to 1,2-diones by Albright–Goldman oxidation.26 Results and discussion

Preparation of dimethoxy[2.n]MCP-1-enes 4 and [2.n]MCP1,2-diols 5 was carried out by following our recent reported procedure by using the tert-butyl group as a positional protective group on the aromatic ring (Scheme 1).27–29 * Correspondent. E-mail: [email protected]

Thus, the AlCl3–MeNO2-catalysed trans-tert-butylation of 1 in benzene at 50°C for 12 h afforded 1,n-bis(2methoxyphenyl)alkanes 2 in good yield. The TiCl4 formylation of compounds 2 with dichloromethyl methyl ether at 20°C gave the desired 1,n-bis(5-formyl-2-methoxyphenyl)alkanes 3 in good yield. 1,3-Bis(5-formyl-2-methoxylphenyl)propane (3a) was subjected to reductive coupling by the McMurry reaction following the improved Grützmacher’s procedure.25 Thus, the reductive coupling reaction of 3a carried out using TiCl4±=QLQWKHSUHVHQFHRIS\ULGLQHLQUHÀX[LQJ7+)XQGHU the high dilution conditions afforded the disired compound 6,13-dimethoxy[2.3]MCP-1-ene (4a) in 23% along with 1,2-dihydroxy-6,13-dimethoxy[2.3]MCP (5a) in 65% yield. Surprisingly, when the present cyclisation reaction was carried out in the absence of pyridine, the yield of 4a increased to 69%. This result was quite different from that of the similar McMurry cyclisation of 1,3-bis(5-acetyl-2-methoxyphenyl)propane, which afforded the corresponding [3.1]MCP by the TiCl4 or acids induced pinacol rearrangements.32–34 Similarly, 6,14dimethoxy[2.4]MCP-1-ene 4b and 1,2-dihydroxy-6,14dimethoxy[2.4]MCP 5b were prepared by the McMurry reaction in 36 and 53% yields, respectively. Interestingly, the increased and preferential formation of [2.4]MCP-1-ene syn-4b in 36% yield was observed in the similar McMurry cyclisation of bis(formyl)diphenylbutane 3b. With increasing the length of the one methylene bridge the higher yield of >Q@0&3HQHZDVREWDLQHG7KLV¿QGLQJVHHPVWRVXSSRUW the notion that the strain of the [2.4]MCP-1-ene compared to the higher [2.3]MCP-1-ene decreases as the length of the one methylene bridge increases. The structures of 4 and 5 were elucidated based on their elemental analyses and spectral data. Especially, the mass spectral data for 4a and 5a (M+ IRU4a and 314 for 5a) strongly supports the cyclic structure. [2.n]MCPs can adopt either a “stair-case” anti conformation or a syn conformation with overlaying aromatic rings (Fig. 1).35,36 Depending on the size of the bridges and on the presence of intraannular substituents, the interconversion between the syn and anti FRQIRUPHUV RFFXU E\ ULQJ ÀLSSLQJ35,36 The conformation of 4 was readily apparent from its 1H NMR spectrum. Thus, WKH LQWHUQDO DURPDWLF SURWRQ VKRZV DQ XS¿HOG VKLIW G 5.95 ppm) due to the ring current of the opposite benzene ring.37,38 The 1H NMR spectrum of the [2.3]MCP-1-ene 4a prepared in the present paper shows that its structure corresponds exclusively to the anti-conformer. In addition, the protons of the trimethylene bridge give rise to two multiplets centred at G   DQG  SSP UHVSHFWLYHO\ SURYLGLQJ D fast interconversion of the two anti conformations of 4a by ULQJÀLSSLQJ+RZHYHUDVWKHWHPSHUDWXUHRIWKHVROXWLRQLQ CDCl3/CS2 (1:3) is decreased, a single peak of the benzyl protons splits into two multiplets at G 1.98 and 2.95 ppm below 10°C. The energy barrier to the conformational ring ÀLSSLQJ HVWLPDWHG IURP WKH FRDOHVFHQFH WHPSHUDWXUH Tc) is 12.8 kcal mol-1. We have assigned the structure of 5a in a similar fashion. Thus, the structure of the anti-confomer is also readily assigned from the chemical shift of the internal

PAPER: 08/5269

480

JOURNAL OF CHEMICAL RESEARCH 2008

OMe

OMe

OMe

AlCl3-MeNO2, Benzene

[CH2]n

OMe [CH2]n

50°C for 12 h 2 a; n= 3 (65%) b; n= 4 (92%)

1 a; n= 3 b; n= 4 OMe

OMe

Cl2CHOMe, TiCl4 CH2Cl2

[CH2)]n

TiCl4-Zn-pyridine in THF reflux for 60 h

room temp. for 1 h CHO

CHO 3 a; n= 3 (65%) b; n= 4 (95%)

MeO

MeO

OH H

[CH2]n

+

[CH2]n H

MeO

OH

MeO 4 a; n= 3 (23%) b; n= 4 (36%)

5 a; n= 3 (65%) b; n= 4 (53%)

Scheme 1

[CH2]n

[CH2]n

anti-conformation Fig. 1

syn-conformation

Possible conformations of [2.n]metacyclophanes.

aromatic protons as a doublet at G 5.95 ppm (J   +]  The other two aromatic protons was observed at G 6.80 and 7.39 ppm; the latter protons are in a strongly deshielding region of oxygen atom of endo-OH on ethylene bridge. These observations are strongly supported that the two OH groups are endo, endo-arrangement and therefore, 5a is found to be trans-diol. In contrast, in the case of 4b WKH DERYH XS¿HOG VKLIW RI the internal aromatic proton was not observed and shifted to ORZHU¿HOGDWG 7.55 ppm due to the deshielding effect from the bridged double bond. This observation strongly suggests 5b adopts syn-conformation different from that in 5a. Table 1 Run

Although Mitchell and Weerawarna22 UHSRUWHG WKH ¿UVW preparation of [2.2]MCP-1,2-dione from oxidation of the corresponding [2.2]MCP-1,2-diol, the physical and chemical properties have not established so far. Thus, there is substantial interest in the oxidation of [2.n]MCPs 4 having a 1,2-diol to afford [2.n]MCP-1,2-diones. An attempted oxidation of the trans-diol 5a to the 1,2-dione 7a with PCC (pyridinium chlorochromate) carried out in a methylene dichloride solution under the same reaction conditions as described above failed. Only the cleavage reaction product, the dicarboxylic acid 8a ZDV REWDLQHG LQ TXDQWLWDWLYH \LHOG 7KLV ¿QGLQJ VHHPV to support the strained nature of the diketone 7a. Swern oxidation39 of 5a using DMSO and oxalyl chloride in CH2Cl2 at –60°C only afforded [2.2]MCP monoketone 6a in only 30% yield along with the ring cleavage reaction product 8a and the starting compound 5a in 20 and 50% yields, respectively (Scheme 2, Table 1). Prolonged reaction time to 24 h at room temperature under the same reaction conditions resulted only a mixture of the [2.3]MCP monoketone 6a and the dicarboxylic acid 8a in almost same ratio. 7KLV ¿QGLQJ VHHPV WR VXSSRUW WKH VWUDLQHG QDWXUH RI WKH diketone 7a compared to the monoketones 6a, in spite of these having the same ring size. Fortunately, theAlbright–Goldman26 oxidation of 5a with DMSO–Ac2O at room temperature for 20 h succeeded in affording the desired [2.3]MCP diketone in

Oxidation of [2.n]metacyclophan-1,2-diols 5 Substrate

Reagents

Products (% yield)a

Time (h) 6

7

8

1 5a PCC 1 0 0 100 2 5a DMSO-(COCl)2b 1 30 0 20 3 5a DMSO-Ac2O 20 0 35c 0 4 5b DMSO-Ac2O 20 0 61 0 aIsolated yields are shown in parenthesis. bThe starting compound 5a was recovered in 50% yield. cIsolated by the reaction of ophenylenediamine to afford [2.3]metacyclophane 9a having a quinoxaline skeleton.

PAPER: 08/5269

JOURNAL OF CHEMICAL RESEARCH 2008 481 HC

MeO

MeO

HB

O 5 a; n= 3 b; n= 4

Oxidation

O

[CH2]n

HA

[CH2]n

+

O

OH MeO

MeO 6 a; n= 3 b; n= 4

7 a; n= 3 b; n= 4 OMe

OMe [CH2)]n

+

COOH

COOH

8 a; n= 3 b; n= 4 Scheme 2

bridge decreases. The structures of the diketones 7a–b, were assigned on the basis of elemental analyses and spectral data. The internal methoxy protons and aromatic protons in the 1H NMR spectrum and the carbonyl frequency in the IR spectrum are tabulated along with the reference compound benzil 10 in Table 1. In the 1H NMR spectrum of 7a, the internal proton (HA) VKRZVDQXS¿HOGVKLIWG 6.12 ppm as a doublet, J +]  due to the ring current of the opposite benzene ring. Thus, its structure corresponds exclusively to the anti-conformer. The two aromatic protons (HB and HC) were observed at G 7.84 (a doublet, J +] DQGSSPGRXEOHGRXEOHWV J    +]  WKH IRUPHU SURWRQV DUH LQ D VWURQJO\ deshielding region of oxigen atom of the bridged carbonyl

35% yield along with the starting compound 5a. However, this diketone 7a was found to be quite labile under treatment by VLOLFDJHOFROXPQFKURPDWURJUDSK\DQGRQUHÀX[LQJLQWROXHQH to afford dicarboxylic acid 8a in quantitative yield. Thus, a trapping reaction of diketone 7a with o-phenylenediamine was attempted, in which the crude diketone 7a was treated with o-phenylenediamine in ethanol at room temperature for 24 h to afford in almost quantitative yield the desired [2.3]MCP 9a having a quinoxaline skeleton (Scheme 3). In contrast, in the case of [2.4]MCP, similar Albright– Goldman oxidation of the trans-diol 5b also succeeded in affording the desired diketone 7b in 61% yield, as stable \HOORZSULVPV7KLV¿QGLQJVHHPVWRVXSSRUWWKHQRWLRQWKDW the strain of the [2.3]diketone 7a compared to [2.4]MCP diketone 7b increases as the length of the one methylene

MeO

H2 N 7 a; n= 3 b; n= 4

N

H2 N [CH2]n

in EtOH room temp. for 24 h (quant)

N MeO 9 a; n= 3 b; n= 4

Scheme 3 Table 2

Spectral data of [2.n]MCP-1,2-diones (7a–b) and reference compound (10)a

Compound

Number of methylene Units, n

Aromatic protons HA

HB

7a 3 6.12 7.84 7b 4 7.51 8.18 10 – – – aDetermined in CDCl by using SiMe as a reference and expressed in ppm. 3 4

PAPER: 08/5269

IR, X (C=O) [cm-1]

Conformation

1685 1667 1662

anti syn

HC 6.92 7.01 –

482

JOURNAL OF CHEMICAL RESEARCH 2008

group. In contrast, in the case of 7b, the aromatic proton (HA) was observed at G 7.51 (a doublet, J +] 7KLVREVHUYDWLRQ strongly suggests that 7b adopts syn-conformation. This ¿QGLQJLQGLFDWHVWKHGLIIHUHQWFRQIRUPDWLRQLVSRVVLEOHLQWKH [2.4]MCP-1,2-dione 7b as the length of the one methylene bridge increases from the [2.3]MCP-1,2-dione 7a. We also observed one of the aromatic protons (HB) to be deshielded by the carbonyl group on the ethylene bridge resulting in a GRZQ¿HOGVKLIWG 8.18 ppm). 7KH KLJKHU IUHTXHQF\ RI & 2 VWUHWFKLQJ YLEUDWLRQ LQ the IR spectrum for [2.4]MCP-1,2-dione 7a (1685 cm-1) in comparison with that for the reference compound benzil 10 (1662 cm-1  SUHVXPDEO\ UHÀHFWV WKH GHYLDWLRQ RI WKH carbonyl group from the plane of the benzene ring rather than conjugation between the carbonyl group and the EHQ]HQHULQJ7KLV¿QGLQJLVVLPLODUWRWKRVHIRUWKHVWUDLQHG [2.2]paracyclophan-1-ones12,40,41 for which absorptions are toward wavelengths characteristic of unconjugated ketones due to the expanded O–C–C bond angles. Similar higher frequency was observed in the higher [2.4]MCP-1,2-dione 7b (1667 cm-1 EXWE\LQFUHDVLQJRQHPHWK\OHQHEULGJHWKH& 2 stretching vibration becomes to appear at the normal positions in [2.4]MCP-1,2-dione 7b. Conclusion

In conclusion, we have developed a convenient preparation of a series of syn- and anti-[2.n]MCP-1-enes 4 and [2.n]MCP1,2-diols 5 by a McMurry cyclisation of 1,n-bis(5-formyl-2methoxyphenyl)alkanes 3. Also, [2.n]MCP-1,2-diols 5 were converted to the 1,2-diones 7 by Albright–Goldman oxidation. Further studies on the chemical properties of the diketones 7 are now in progress. Experimental 1H

NMR spectra were recorded at 300 MHz on a Nippon Denshi JEOL FT-300 NMR spectrometer in deuteriochloroform with Me4Si as an internal reference. IR spectra were measured as KBr pellets on a Nippon Denshi JIR-AQ2OM spectrometer. Mass spectra were obtained on a Nippon Denshi JMS-HX110A Ultrahigh Performance Mass Spectrometer at 75 eV using a direct-inlet system. Elemental analyses were performed by Yanaco MT-5. Materials Preparations of 1,n-bis(5-tert-butyl-2-methoxyphenyl)alkanes 1 was previously described.30,31 Trans-tert-butylation of 1a to give 2a: To a solution of 1a (2.21 g, 6.0 mmol) in benzene (16 cm3) was added a solution of anhydrous aluminum chloride (1.60 g, 12.0 mmol) in nitromethane (3.2 cm3). After the reaction mixture was stirred for 12 h at 50°C, the reaction was quenched by the addition of 10% hydrochloric acid, and the solution was washed with water, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (Wako C-300, 300 g) with hexane–benzene (1 : 1) as eluent to give crude 2a as a colourless solid. Recrystallisation from petroleum ether gave 1,3-bis(2-methoxyphenyl)propane (2a) (1.0 g, 65%) as a colourless prisms, m.p. 63–65°C; Qmax(KBr)/cm-1: 3000, 2939, 2856, 1601, 1588, 1494, 1466, 1434, 1325, 1291, 1242, 1174, 1158, 1049, 1026, 927, 828, 756; GH (CDCl3) 1.83–1.95 (2H, m, ArCH2CH2CH2Ar), 2.67 (4H, t, J   +]$UCH2CH2CH2Ar), 3.77 (6 H, s, OMe), 6.79–6.88 (4H, m, ArH), 7.12–7.17 (4H, m, ArH); m/z: 256 (M+) (Found: C, 79.45; H, 7.58. C17H20O2 (256.34) requires C, 79.65; H, 7.86%). 2b: Prepared as described for 2a in 92% yield. 1,4-Bis(2-methoxyphenyl)butane (2b) was obtained as colourless prisms (petroleum ether); m.p. 74–76°C; Qmax(KBr)/cm-1: 3000, 2939, 2856, 1601, 1588, 1494, 1466, 1434, 1325, 1291, 1242, 1174, 1158, 1049, 1026, 927, 828, 756; GH (CDCl3) 1.61–1.67 (4H, m, ArCH2CH2CH2CH2Ar), 2.64 (4H, t, J +]$UCH2CH2CH2Ar), 3.80 (6 H, s, Me), 6.81– 6.89 (4H, m, ArH), 7.11–7.18 (4H, m, ArH); m/z: 270 (M+) (Found: C, 80.23; H, 8.33. C18H22O2 (270.37) requires C, 79.96; H, 8.20%). 3a: To a solution of 2a (1.15 g, 4.5 mmol) and Cl2CHOCH3 (1.14 cm3, 12.6 mmol) in CH2Cl2 (10 cm3) was added a solution of

TiCl4 (3.0 cm3, 27.3 mmol) in CH2Cl2 (10 cm3) at 0°C. After the reaction mixture was stirred at room temp. for 1 h, it was poured into a large amount of ice/water (50 cm3) and extracted with CH2Cl2 (2 u20 cm3). The combined extracts were washed with water, dried with Na2SO4 and concentrated. The residue was chromatographed over silica gel (Wako C–300, 200 g) with benzene as eluent to give 3a (914 mg, 65%) as a colourless solid. Recrystallisation from hexane gave 1,3-bis(5-formyl-2-methoxyphenyl)propane 3a as colourless prisms, m.p. 82–84°C; Qmax (KBr)/cm-1  & 2  GH(CDCl3) 1.90–1.96 (m, 2 H, ArCH2CH2CH2Ar), 2.71 (4H, t, J   +] $UCH2CH2CH2Ar), 3.91 (6 H, s, OMe), 6.91 (2H, d, J +]$UH), 7.70 (2H, d, J +]$UH), 7.72 (2H, dd, J  7.8 Hz), 9.86 (2H, s, CHO); m/z: 312 (M + ) (Found C, 72.85; H, 6.55. C19H20O4 (312.37) requires C, 73.06; H, 6.45%). 3b: Prepared as described for 3a in 95% yield. 1,4-Bis(5-formyl2-methoxyphenyl)butane (3b) was obtained as colourless prisms (petroleum ether); m.p. 95–97°C; Qmax (KBr)/cm-1  & 2  GH(CDCl3) 1.61–1.18 (4H, m, ArCH2CH2CH2CH2Ar), 2.69 (4H, t, J   +] $UCH2CH2CH2Ar), 3.96 (6 H, s, OMe), 6.94 (2H, d, J   +] $UH), 7.67 (2H, d, J   +] $UH), 7.70 (2 H, dd, J +]$UH), 9.85 (2H, s, CHO); m/z: 326 (M + ) (Found C, 73.53; H, 6.89. C20H22O4 (326.4) requires C, 73.59; H, 6.79%). McMurry coupling reaction of 3 The McMurry reagent was prepared from TiCl4 [23.8 g (13.8 cm3), 125 mmol] and Zn powder (18 g, 275 mmol) in dry THF (500 cm3) under nitrogen. A solution of 1,3-bis(5-formyl-2methoxyphenyl)propane 3a (2.81 g, 9.0 mmol) and pyridine (22.8 cm3, 200 mmol) in dry THF (250 cm3) was added within 60 h to the black mixture of the McMurry reagent by using a highGLOXWLRQ WHFKQLTXH ZLWK FRQWLQXRXV UHÀX[LQJ DQG VWLUULQJ 7KH UHDFWLRQ PL[WXUH ZDV UHÀX[HG IRU DGGLWLRQDO  K FRROHG WR URRP temperature, and treated with aqueous 10% K2CO3 (200 cm3) at 0°C. The reaction mixture was extracted with CH2Cl2 (3u200 cm3). The combined extracts were washed with water, dried with Na2SO4 and concentrated. The residue was chromatographed over silica gel (Wako C-300, 300 g) with hexane–benzene (2:1) and CHCl3–EtOAc (1 : 1) as eluents to give 4a (590 mg, 23%) and 5a (1.84 g, 65%) as a colourless solid, respectively. 6,13-Dimethoxy[2.3]metacyclophan-1-ene 4a: Colourless prisms (from methanol), m.p. 133–135°C; Qmax (KBr)/cm-1 2936, 2898, 2833, 1601, 1496, 1438, 1288, 1248, 1187, 1127, 1032, 948, 815, 783; GH(CDCl3, 27°C) 1.93–1.98 (2H, m, ArCH2CH2CH2Ar), 2.35 (4H, broad s, ArCH2CH2CH2Ar), 3.82 (6H, s, OMe), 5.95 (2H, d, J   +] $UH), 6.58 (2H, s, CH), 6.68 (2H, d, J   +] ArH), 6.93 (2H, dd, J    +] $UH); GH(CDCl3/CS2, 1 : 3, –40°C) 0.82–0.92 (1H, m, ArCH2CH2CH2Ar), 1.71–0.84 (1H, m, ArCH2CH2CH2Ar), 1.93–2.03 (2H, m, ArCH2CH2CH2Ar), 2.90–3.02 (2H, m, ArCH2CH2CH2Ar), 3.82 (6H, s, OMe), 5.95 (2H, d, J +] ArH), 6.58 (2H, s, CH), 6.68 (2H, d, J   +]$UH), 6.93 (2H, dd, J +]$UH); m/z: 280 (M + ) (Found C, 81.32; H, 7.31. C19H20O2 (280.37) requires C, 81.40; H, 7.19%). 1-endo-2-endo-dihydroxy-6,13-dimethoxy[2.3]metacyclophane 5a: Colourless prisms (from petroleum ether), m.p. 218–219°C; Qmax (KBr)/cm-1 3563, 3327 (OH), 2941, 1608, 1502, 1244, 1128, 1027, 825, 615; GH(CDCl3) 1.80–1.95 (2H, broad s, ArCH2CH2CH2Ar), 1.98–2.12 (2H, m, ArCH2CH2CH2Ar), 2.75 (2H, s, OH), 2.94–3.05 (2H, m, ArCH2CH2CH2Ar), 3.82 (6H, s, OMe), 4.34 (2H, s, CH), 4.99 (2H, d, J = 2.4 Hz, ArH), 6.80 (2H, d, J +]$UH), 7.39 (2H, dd, J +]$UH); m/z: 314 (M + ) (Found C, 72.53; H, 7.06. C19H22O4 (314.38) requires C, 72.59; H, 7.05%). Similarly, compounds 4b and 5b were prepared in the same manner as described above in 36 and 53% yields, respectively. 6,14-Dimethoxy[2.4]metacyclophan-1-ene 4b: Colourless prisms (from methanol), m.p. 117–119°C; Qmax (KBr)/cm-1 2954, 2912, 2835, 1500, 1263, 1245, 1116, 1029, 824; GH(CDCl3) 1.18–1.32 (2H, m, ArCH2CH2CH2CH2Ar), 1.52–1.68 (2H, m, ArCH2CH2CH2CH2Ar), 2.23–2.38 (2H, broad s, ArCH2CH2CH2CH2Ar), 2.75–2.93 (2H, broad s, ArCH2CH2CH2CH2Ar), 3.81 (6H, s, OMe), 6.39 (2H, s, CH), 6.77 (2H, d, J +]$UH), 6.98 (2H, dd, J +]$UH), 7.55 (2H, d, J $UH); m/z: 294 (M + ) (Found C, 81.69; H, 7.53. C20H22O2 (294.39) requires C, 81.60; H, 7.53%). 1-endo-2-endo-Dihydroxy-6,14-dimethoxy[2.4]metacyclophane 5b: Colourless needles (from CH2Cl2), m.p. 218–219°C; Qmax (KBr)/ cm-1 3558 3386 (OH), 2931, 2863, 1250, 1182, 1111, 1079, 1056; GH(CDCl3) 0.75–1.68 (2H, broad s, ArCH2CH2CH2CH2Ar), 1.41– 1.65 (2H, broad s, ArCH2CH2CH2CH2Ar), 2.09–2.38 (2H, broad s, ArCH2CH2CH2CH2Ar), 2.85 (2H, s, OH), 2.72–3.10 (2H, broad s,

PAPER: 08/5269

JOURNAL OF CHEMICAL RESEARCH 2008 483 ArCH2CH2CH2CH2Ar), 3.82 (6H, s, OMe), 4.34 (2H, s, CH), 5.78 (2H, broad s, ArH), 6.90 (2 H, d, J +]$UH), 7.56 (2H, broad d, ArH); m/z: 314 (M + ) (Found C, 73.03; H, 7.23. C20H24O4 (328.41) requires C, 73.15; H, 7.37%). Oxidation of 5a with PCC: To a solution of 5a (100 mg, 0.32 mmol) and acetone (5 cm3) was added PCC (157 mg, 0.73 mmol) at 0°C. The reaction mixture was stirred at room temperature for 24 h. The UHDFWLRQ PL[WXUH ZDV ¿OWHUHG DQG WKH ¿OWUDWH H[WUDFWHG ZLWK &+2Cl2 (3u10 cm3). The extract was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica-gel (Wako, C-300; 100 g) column chromatography using as eluent benzene to give dicarboxylic acid (8a) (105 mg, 95%) as a colourless solid. Recrystallisation from benzene afforded 8a as colourless prisms, m.p. 241–242°C; Qmax (KBr)/cm-1 ± 2+   & 2   1502, 1447, 1306, 1251, 722, 632; GH (CDCl3): 1.74–1.88 (2H, m, CH2CH2CH2), 2.55–2.68 (4H, m, CH2CH2CH2), 3.83 (6 H, s, OMe), 7.02 (2H, d, J = 8.7 Hz, ArH), 7.71 (2H, d, J = 1.0 Hz, ArH), 7.82 (2H, dd, J +] +VOH); m/z: 344 (M + ) (Found C, 66.39; H, 5.897. C19H20O6 (344.37) requires C, 66.27; H, 5.85%). Swern oxidation of 5a: To a solution of of oxalyl chloride (0.25 cm3, 2.75 mmol) in CH2Cl2 (25.0 cm3) was added DMSO (0.126 cm3, 1.65 mmol) and then 5a (110 mg, 0.35 mmol) in CH2Cl2 (1.0 cm3) at –30°C under nitrogen. After the reaction mixture had been stirred at –30°C for 1 h, triethylamine (380 mg, 3.75 mmol) was added. The temperature of the reaction mixture was maintained at –30°C for 30 min. under nitrogen, then allowed to warm to room temp. and stirred for an additional 1 h. Then, water (10 cm3) was added and the reaction mixture was extracted with CH2Cl2 (3 u 10 cm3). The dichloromethane solution was washed with water, dried over Na2SO4, and evaporated in vacuum to a residue. 1H NMR spectrum of this oil was in accord with its being a mixture of three components, 5a, 6a, and 8a in the ratio of 50:30:20. 6a: GH (CDCl3): 1.67–1.85 (2H, m, CH2CH2CH2), 2.00–2.14 (2H, m, CH2CH2CH2), 2.85–3.00 (2H, m, CH2CH2CH2), 3.75 (3H, s, OMe), 3.88 (3H, s, OMe), 3.89 (1H, s, OH), 4.66 (1H, s, CH), 5.05, 5.55 (2H, each d, J = 1.0 Hz, ArH, H8,17), 6.65, 6.85 (2H, each d, J = 8.3 Hz, ArH, H5,14), 7.35, 7.65 (2H, each dd, J = 1.0, 8.3 Hz, ArH, H4,15). Albright–Goldman oxidation of 5a: To a solution of acetic anhydride (0.6 cm3) and 5a (110 mg, 0.35 mmol) was added DMSO (0.9 cm3, 12.6 mmol) at room temperature. After the reaction mixture had been stirred at room temperature for 20 h, ethanol (0.5 cm3) and triethylamine (2 cm3, 14.2 mmol) was added and stirred for an additional 30 min. Then, water (5 cm3) was added and the reaction mixture was extracted with CH2Cl2 (3u5 cm3). The dichloromethane solution was washed with water, dried over Na2SO4, and evaporated in vacuum to a residue. 1H NMR spectrum of this oil was in accord with its being a mixture of three components, 5a and 7a in the ratio of 35:65, which was crystallised by adding a small amount of hexane–CH2Cl2, 5:1 to give a pale yellow solid. The solid was washed with hexane–CH2Cl2, 10 : 1 to afford crude 6,13-dimethoxy[2.3]metacyclophane-1,2-dione 7a in 38 mg (35%) as pale yellow solid; Qmax (KBr)/cm-1& 2 GH (CDCl3): 1.80 (2H, broad s, CH2), 2.0–2.4 (4H, m, CH2), 3.97 (6H, s, OMe), 6.12 (2H, d, J +]$UHA), 6.92 (2H, d, J +]$UHC), 7.84 (2H, dd, J = 1.0, 8.3 Hz, ArHB); m/z: 310 (M + ). However, attempted isolation of 7a pure failed. Thus, diketone 7a was found to be quite labile under treatment by silica gel column FKURPDWURJUDSK\ DQG RQ UHÀX[LQJ LQ WROXHQH WR DIIRUG GLFDUER[\OLF acid 8a in quantitative yield as colourless solid. Trapping reaction of 7a with o-phenylenediamine: To a solution of crude 7a (10.6 mg, 0.034 mmol) in ethanol (10 cm3) was added o-phenylenediamine (3.7 mg, 0.034 mmol) at room temperature. After the reaction mixture had been stirred at room temperature for 24 h, the solvent was evaporated in vacuum to leave a residue. The residue was washed successively with 10% aqueous hydrochloric acid, water, and ethanol to afford 9a (13 mg, 100%) as a brown solid, m.p. >300°C; GH (CDCl3): 1.88 (2H, broad s, ArCH2CH2CH2Ar), 2.0 (2H, broad s, ArCH2CH2CH2Ar), 3.00 (2H, broad s, ArCH2CH2CH2Ar), 3.90 (6H, s, OMe), 5.95 (2H, d, J +]$UH, H8,17), 6.82 (2H, d, J +]$UH, H5,14), 7.53 (2H, dd, J = 1.0, 8.3 Hz, ArH, H4,15), 7.65 (2H, dd, J = 3.4, 6.3 Hz, ArH) and 8.06 (2H, dd, J = 3.4, 6.3 Hz, ArH); m/z: 382 (M + ) (Found C, 78.25; H, 5.93; N, 7.38. C25H22N2O2 (382.47) requires C, 78.51; H, 5.8; N, 7.32%). Albright–Goldman oxidation of 5b: To a solution of acetic anhydride (2.5 cm3) and 5b (440 mg, 1.34 mmol) was added DMSO (3.78 cm3, 53.2 mmol) at room temperature. After the reaction mixture had been stirred at room temperature for 20 h, ethanol (2 cm3) and triethylamine (8.4 cm3, 60 mmol) was added and stirred for an additional 30 min. Then, water (10 cm3) was added and the reaction mixture was extracted with CH2Cl2 (3 u 10 cm3).

The dichloromethane solution was washed with water, dried over Na2SO4, and evaporated in vacuum to a residue. The residue was crystallised by adding a small amount of hexane–CH2Cl2, 5:1 to give a yellow solid. Recrystallisation from hexane–CH2Cl2, 10:1 afforded 6,14-dimethoxy[2.4]metacyclophane-1,2-dione 7b (265 mg, 61%) as yellow prisms, m.p. 182°C; Qmax (KBr)/cm-1  & 2  GH (CDCl3): 1.13 (2H, broad s, ArCH2CH2CH2CH2Ar), 1.66 (2H, broad s, ArCH2CH2CH2CH2Ar), 2.32 (2H, broad s, ArCH2CH2CH2CH2Ar), 2.92 (2H, broad s, ArCH2CH2CH2CH2Ar), 3.95 (6H, s, OMe), 7.01 (2H, d, J +]$UHC), 7.51 (2H, d, J = 2.4 Hz, ArHA), 8.18 (2H, dd, J = 2.4, 8.7 Hz, ArHB); m/z: 324 (M + ). (Found C, 73.93; H, 6.17. C20H20O4 (324.37) requires C, 74.06; H, 6.21%). Similarly, compound 9b was prepared in 100% yield. Compound 9b was obtained as yellow prisms (hexane), m.p. 262– 263°C; Qmax (KBr)/cm-1: 1602, 1500, 1342, 1292, 1118, 761; GH (CDCl3): 1.18–1.21 (4H, m, ArCH2CH2CH2CH2Ar), 2.56 (4H, broad s, ArCH2CH2CH2CH2Ar), 3.80 (6H, s, OMe), 6.96 (2H, d, J +] ArH, H5,15), 6.97 (2H, d, J = 2.2, ArH, H8,18), 7.64 (2H, dd J = 3.4, 6.3 Hz, ArH), 7.78 (2H, d, J +]$UH, H4,16), 8.09 (2H, dd, J = 3.4, 6.3 Hz, ArH); m/z: 396 (M + ) (Found C, 78.50; H, 6.14; N, 7.13. C26H24O2N2 (396.49) requires C, 78.76; H, 6.10; N, 7.07%).

Received 8 May 2008; accepted 25 June 2008 Paper 08/5269 doi: 10.3184/030823408X338701 Published online: 26 August 2008 References 1   3 4 5 6 7   9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

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PAPER: 08/5269